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Adenine Phosphoribosyltransferase Deficiency

Synonyms: 2,8-Dihydroxyadeninuria; APRT Deficiency

, MD, , MD, and , PhD.

Author Information

Initial Posting: ; Last Update: June 18, 2015.

Summary

Clinical characteristics.

Adenine phosphoribosyltransferase (APRT) deficiency is characterized by excessive production of 2,8-dihydroxyadenine (DHA), which is excreted in the urine, where it is poorly soluble and leads to kidney stone formation and chronic kidney disease (CKD). Kidney stones, the most common clinical manifestation of APRT deficiency, can occur at any age; in at least 50% of affected individuals symptoms do not occur until adulthood. In a significant number of individuals, intratubular and interstitial precipitation of DHA crystals can result in kidney failure (i.e., DHA crystal nephropathy).

Diagnosis/testing.

The detection of the characteristic round, brown DHA crystals by urine microscopy is highly suggestive of the disorder. The diagnosis is confirmed by absence of APRT enzyme activity in red cell lysates or identification of biallelic pathogenic variants in APRT.

Management.

Treatment of manifestations: Treatment with the xanthine dehydrogenase (XDH) inhibitor allopurinol can prevent or dissolve kidney stones and improve kidney function, even in individuals with advanced CKD. The XDH inhibitor febuxostat is an alternative option for those allergic to or intolerant of allopurinol. A low purine diet and ample fluid intake are recommended. Surgical management of DHA nephrolithiasis is the same as for other types of kidney stones. End-stage renal disease is treated with dialysis and kidney transplantation.

Prevention of primary manifestations: Lifelong treatment with allopurinol (or febuxostat) prevents or attenuates DHA crystalluria, nephrolithiasis, crystal nephropathy, and the development of kidney failure. The prescribed allopurinol dose should not routinely be reduced in affected individuals who have impaired kidney function.

Surveillance: Routine follow-up to facilitate medication compliance; consideration of periodic renal ultrasound examination to evaluate for new kidney stones.

Agents/circumstances to avoid: Azathioprine should be avoided by individuals taking XDH inhibitors.

Evaluation of relatives at risk: It is recommended that sibs of an affected individual undergo APRT enzyme activity measurement or molecular genetic testing (if the pathogenic variants in a family have been identified) to allow early diagnosis and treatment and improve long-term outcome.

Pregnancy management: The safety of allopurinol in human pregnancy has not been systematically studied. Some post-transplantation immunosuppressive therapies can have adverse effects on the developing fetus. Ideally a thorough discussion of the risks and benefits of maternal medication use during pregnancy should take place with an appropriate health care provider prior to conception.

Genetic counseling.

APRT deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being normal. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants in the family have been identified.

Diagnosis

Suggestive Findings

Adenine phosphoribosyltransferase (APRT) deficiency (also known as 2,8-dihydroxyadeninuria) should be suspected in individuals with the following clinical, radiographic, laboratory, and pathology findings [Edvardsson et al 2001, Bollée et al 2010, Nasr et al 2010, Edvardsson et al 2013]:

Clinical manifestations

  • A history of reddish-brown diaper stain, a frequent manifestation of DHA crystalluria in infants.
  • Renal colic
  • Chronic kidney disease (CKD) of unknown cause
  • Crystal nephropathy
  • Unexplained acute kidney injury (particularly in individuals with a history of radiolucent kidney stones)

Radiographic findings

  • Radiolucent kidney stones (based on imaging techniques capable of detecting radiolucent stones, e.g., ultrasound or computed tomography [CT]; stones are not seen on a plain abdominal x-ray)

Laboratory findings

  • Urinalysis
    • Urine microscopy. The pathognomonic round and brown DHA crystals can usually be detected by urine microscopy (Figure 1A). Small and medium sized DHA crystals display a central Maltese cross pattern when viewed by polarized light microscopy (Figure 1B).

      Note: (1) DHA crystals may be difficult to identify in individuals with advanced CKD, possibly due to reduced clearance of the crystals by the kidney [Edvardsson et al 2001, Bollée et al 2010]. (2) High urine pH in individuals with radiolucent stones provides an additional clue to the diagnosis of APRT deficiency because uric acid stones develop in acidic urine (see Differential Diagnosis).
    • Testing for DHA. DHA can be identified in urine samples by high-performance liquid chromatography (HPLC) with UV detection or HPLC coupled with mass spectrometry.
  • Kidney stone analysis. Analysis of DHA crystals and kidney stone material using infrared or ultraviolet spectrophotometry (at both acidic and alkaline pH) and/or x-ray crystallography easily differentiates DHA from uric acid and xanthine, which also form radiolucent stones. Although stones in persons with APRT deficiency are predominantly composed of DHA, they may contain trace amounts of uric acid.
    Note: Stone analysis with standard chemical and thermogravimetric methods does not distinguish DHA from other purines (e.g., uric acid) and is no longer recommended.
Figure 1. . Urinary 2,8-dihydroxyadenine (DHA) crystals from an individual with adenine phosphoribosyltransferase deficiency.

Figure 1.

Urinary 2,8-dihydroxyadenine (DHA) crystals from an individual with adenine phosphoribosyltransferase deficiency. These crystals have a characteristic appearance and polarization pattern. A. Conventional light microscopy shows the typical brown DHA crystals. (more...)

Pathology

  • Renal histopathologic examination. Renal histopathologic findings in persons with APRT deficiency and CKD or acute allograft dysfunction are characterized by diffuse DHA crystal deposits and tubulointerstitial abnormalities, even in the absence of a history of kidney stones (see Figure 2) [Edvardsson et al 2001, Zaidan et al 2014].
    Note: It is important not to confuse the histopathologic manifestations of crystal nephropathy caused by APRT deficiency with those of other crystal nephropathies, particularly those caused by oxalate and uric acid deposits [Nasr et al 2010].
Figure 2. . Kidney biopsy findings from an individual with adenine phosphoribosyltransferase deficiency and kidney failure due to 2,8- dihydroxyadenine crystal nephropathy A.

Figure 2.

Kidney biopsy findings from an individual with adenine phosphoribosyltransferase deficiency and kidney failure due to 2,8- dihydroxyadenine crystal nephropathy A. 2,8-dihydroxyadenine (DHA) crystals are seen within tubular lumens (arrows). Significant (more...)

Establishing the Diagnosis

The diagnosis of APRT deficiency is established in a proband with the above suggestive findings and absent APRT enzyme activity in red cell lysates or by the identification of biallelic APRT pathogenic variants. A diagnostic algorithm is presented in Figure 3 [Edvardsson et al 2013].

Figure 3. . Algorithm for diagnostic evaluation of adenine phosphoribosyltransferase (APRT) deficiency and 2,8-dihydroxyadeninuria From Edvardsson et al 2013.

Figure 3.

Algorithm for diagnostic evaluation of adenine phosphoribosyltransferase (APRT) deficiency and 2,8-dihydroxyadeninuria From Edvardsson et al 2013. Used by permission.

APRT enzyme activity. APRT activity measured in red cell lysates ranges from 16 to 32 nmol/hr per mg hemoglobin in healthy individuals.

APRT enzyme activity measured in red cell lysates (or other cell extracts) is absent in almost all individuals with APRT deficiency; however, exceptions occur. For example, two enzyme isoforms resulting from the following APRT pathogenic variants have substantial activity in red cell lysates:

Thus, in individuals with these pathogenic variants, in vivo assays (e.g., uptake of adenine by intact erythrocytes or leukocytes) are required to verify APRT deficiency.

Note: (1) If enzyme activity is within normal limits or in the heterozygote range in an individual who has recently received a red cell transfusion, enzyme activity measurement should be repeated after three months. (2) Heterozygotes for an APRT pathogenic variant cannot be reliably identified by enzyme assay in cell extracts as the enzyme activity range in these individuals overlaps with that of controls.

Molecular testing approaches include single-gene testing.

1.

Sequence analysis of APRT should be performed first.

2.

If only one or no pathogenic variant is identified on sequence analysis, gene-targeted deletion/duplication analysis can be performed.

Table 1.

Molecular Genetic Testing Used in Adenine Phosphoribosyltransferase Deficiency

Gene 1Test MethodProportion of Probands with a Pathogenic Variant2 Detectable by This Method
APRTSequence analysis 3, 4>95% 5
Gene-targeted deletion/duplication analysis 6See footnote 7
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

More than 40 pathogenic variants have been identified in the coding region of APRT in over 300 affected individuals from more than 25 countries, including at least 200 individuals from Japan (see Molecular Genetics).

5.

Pathogenic variants in APRT have not been identified in at least five individuals with APRT deficiency and it remains to be determined whether these pathogenic variants occur outside of the APRT coding region or are due to epigenetic changes.

6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used can include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

7.

Four described deletions include (see Molecular Genetics): a large homozygous contiguous gene deletion (~100 kb) [Wang et al 1999] a 254-kb deletion in two families (one from Austria and the other from Italy) [Menardi et al 1997, Di Pietro et al 2007], and an uncharacterized large deletion in two individuals from Japan [Kamatani et al 1992].

Note that enzyme activity measurements in cell extracts alone may not be sufficient to determine the functional significance of novel variants. (See APRT enzyme activity.)

Clinical Characteristics

Clinical Description

Kidney stones are the most common clinical manifestation of APRT deficiency in both children and adults [Edvardsson et al 2001, Harambat et al 2012] and CKD is the second most common manifestation in adults [Edvardsson et al 2001, Harambat et al 2012]. Acute kidney injury due to bilateral DHA calculi and urinary tract obstruction is a well-recognized presentation in children [Debray et al 1976, Greenwood et al 1982, Chiba et al 1988, Edvardsson et al 2001].

APRT deficiency may present at any age; there is no typical age of onset. In a recently reported French series [Bollée et al 2010], only 37% of individuals with APRT deficiency were diagnosed before age 16 years. The median (range) age at diagnosis in 33 Icelandic individuals with data in the APRT Deficiency Registry of the Rare Kidney Stone Consortium was 27.3 (0.6-62.7) years. Sixteen (48%) of these 33 individuals first presented in childhood (<18 years) at a median age of 2.2 (0.2-16.5) years [unpublished observations].

Many children, however, remain asymptomatic and in at least half of instances the diagnosis of APRT deficiency is not made until adulthood. Of note, abdominal ultrasound and CT examinations performed for other reasons may identify kidney stones in individuals with APRT deficiency who may be asymptomatic. In a significant number of asymptomatic individuals, APRT deficiency has been diagnosed by the detection of DHA crystals on routine urine microscopy or through the screening of sibs of affected individuals [Edvardsson et al 2001, Harambat et al 2012].

The majority of symptomatic individuals with APRT deficiency experience recurrent DHA kidney stones, abdominal pain, and/ or lower urinary tract symptoms for years. They also frequently develop CKD secondary to DHA crystal nephropathy in which the crystals are typically located in tubular lumina, inside renal epithelial cells, and in the interstitium.

Studies have shown that 15% of individuals had progressed to end-stage renal disease (ESRD) at the time of diagnosis of APRT deficiency [Edvardsson et al 2001, Bollée et al 2010, Harambat et al 2012]. In some of these individuals the diagnosis was not made until after kidney transplantation [Benedetto et al 2001, Cassidy et al 2004, Zaidan et al 2014].

APRT deficiency is not known to affect organs other than the kidney; however, the authors and other investigators have encountered occasional individuals with APRT deficiency complaining of eye discomfort [Neetens et al 1986; Author, personal observation], which merits further study.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been established; clinical features are known to vary greatly between individuals with the same pathogenic variants [Edvardsson et al 2001, Bollée et al 2010].

Nomenclature

Originally, two types of APRT deficiency with identical clinical manifestations were described, based on the level of residual APRT activity in cell extracts (erythrocyte lysates) [Sahota et al 2001]. However, this distinction is of historic interest only, as APRT enzyme activity in intact cells has been shown to be less than 1% in both types [Kamatani et al 1985] (See Establishing the Diagnosis, APRT enzyme activity).

Prevalence

The estimated heterozygote frequency in different populations ranges from 0.4 to 1.2% [Hidaka et al 1987, Sahota et al 2001], suggesting that the prevalence of a homozygous state is at least 1:50,000 to 1:100,000.

If this holds true, at least 70,000-80,000 individuals should be affected worldwide, of whom 40,000 would be expected to be in Asia, 9000 in Europe, and 8000 in the Americas, including at least 3000 affected individuals in the US alone. Most of these individuals are currently unrecognized (and thus, not benefitting from medical therapy).

Evidence suggests that APRT deficiency may be a seriously underrecognized cause of kidney stones and crystal nephropathy, progressing over time to ESRD in a significant proportion of untreated individuals [Zaidan et al 2014].

Differential Diagnosis

Differential diagnosis of APRT deficiency includes other known causes of radiolucent kidney stones such as uric acid nephrolithiasis (OMIM 605990) and xanthinuria (OMIM 278300, 603592).

The diagnosis of APRT deficiency should be considered in all individuals with CKD or kidney failure, particularly in those with renal histopathologic features of crystal nephropathy, even in the absence of a history of nephrolithiasis.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with APRT deficiency, the following evaluations are recommended:

  • Assessment of kidney involvement:
    • Measure serum creatinine concentration.
    • Screen for albuminuria or proteinuria.
    • Assess kidney stone burden with ultrasound or CT examination.
    • Perform kidney biopsy in individuals with reduced renal function and/or proteinuria.
  • Ophthalmology consultation if eye symptoms are present
  • Consideration of consultation with a medical geneticist and/or genetic counselor

Treatment of Manifestations

Allopurinol. Treatment with the XDH inhibitor allopurinol is effective and generally well-tolerated in individuals with APRT deficiency. Allopurinol 5-10 mg/kg/day (maximum daily dose 800 mg), either once daily or in two divided doses, minimizes DHA crystalluria, stone formation, crystal deposition in the kidney, and the development of kidney failure [Edvardsson et al 2001, Bollée et al 2010]. Treatment with allopurinol can even dissolve DHA kidney stones and improve kidney function in individuals with advanced CKD [Edvardsson et al 2001, Bollée et al 2010]. Allopurinol treatment is monitored by clinical evaluation and urine microscopy; the absence of urinary DHA crystals is indicative of adequate therapy.

Febuxostat. The recently introduced XDH inhibitor febuxostat provides an alternative treatment option for affected individuals allergic to or intolerant of allopurinol [Becker et al 2005]. The complete disappearance of urinary DHA crystals was recently described in an indvidual with APRT deficiency treated with febuxostat in the daily dose of 80 mg [Arnadóttir 2014]. Furthermore, the authors of this review have noted a significant reduction or even disappearance of DHA crystalluria in several adult individuals with APRT deficiency treated with a daily febuxostat dose of 80 mg [unpublished observations].

Low purine diet and ample fluid intake provide adjunctive benefits to pharmacologic therapy.

Surgical management of DHA kidney stones is the same as for the management of other types of stones, including extracorporeal shock-wave lithotripsy.

Treatment of ESRD

  • Dialysis. Of note, it is not known if individuals with APRT deficiency on dialysis benefit from allopurinol therapy. The allopurinol dose should not routinely be reduced in affected individuals who have impaired kidney function.
  • Kidney transplantation. All individuals with APRT deficiency undergoing kidney transplantation require treatment with allopurinol (or febuxostat) for at least six weeks prior to transplant surgery, whenever possible. Affected individuals who have undergone kidney transplantation require lifelong therapy with allopurinol (or febuxostat) to prevent recurrent DHA crystal nephropathy in the transplanted organ.

Prevention of Primary Manifestations

Adequate treatment of APRT deficiency with allopurinol (or febuxostat in those who are allergic to or intolerant of allopurinol) prevents kidney stone formation and the development of CKD in most, if not all, individuals with the disorder [Edvardsson et al 2001, Bollée et al 2010, Harambat et al 2012]. Therefore, all affected individuals should receive lifelong treatment with allopurinol (or febuxostat).

Surveillance

No surveillance guidelines have been developed. However, all individuals with APRT deficiency should see their physician every six to 12 months to:

  • Monitor kidney function;
  • Assess the urinary excretion of DHA crystals (disappearance of the crystals is considered an adequate treatment response);
  • Facilitate medication compliance.

Periodic renal ultrasound examinations may be considered to evaluate for new kidney stones.

Agents/Circumstances to Avoid

Azathioprine should be avoided by individuals taking XDH inhibitors.

Evaluation of Relatives at Risk

Once the pathogenic variants in a family have been identified, it is recommended that sibs of an affected individual undergo molecular genetic testing or APRT enzyme activity measurements to allow early diagnosis and treatment in order to improve long-term outcome. Further investigations, including assessment of renal function and urinalysis, are warranted in individuals with biallelic pathogenic variants.

Note: Approximately 15% of individuals with APRT deficiency may be asymptomatic [Edvardsson et al 2001, Bollée et al 2010]; they are usually identified during family screening.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

The safety of allopurinol in human pregnancy has not been systematically studied.

Animal studies using high doses of allopurinol have revealed evidence of adverse fetal effects in mice but not in rats or rabbits; it is not clear if these effects are a result of direct fetal toxicity or maternal toxicity. Thus, allopurinol should only be prescribed during pregnancy when the benefit of treatment is believed to outweigh the risk. Treatment with allopurinol during pregnancy should be considered in women with APRT deficiency who have CKD with reduced glomerular filtration rate (GFR) or who have undergone kidney transplantation.

Some post-transplantation immunosuppressive therapies can also have adverse effects on the developing fetus.

A thorough discussion of the risks and benefits of maternal medication use during pregnancy should ideally take place with an appropriate health care provider prior to conception.

Therapies Under Investigation

Search Clinical Trials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

APRT deficiency is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected individual are obligate heterozygotes (i.e., carriers of one APRT pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic, urine microscopy does not reveal DHA crystals, and they are not at risk of developing the disorder.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of inheriting two APRT pathogenic variants, a 50% chance of inheriting one pathogenic variant and being an asymptomatic carrier, and a 25% chance of inheriting two benign alleles.
  • Approximately 15%-20% of individuals who have inherited two APRT pathogenic variants may be asymptomatic despite their abnormal urinary DHA excretion [Edvardsson et al 2001, Bollée et al 2010]. Such individuals are usually identified during family screening.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier of an APRT pathogenic variant is 2/3.
  • Heterozygotes (carriers) are asymptomatic, urine microscopy does not reveal DHA crystals, and they are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with APRT deficiency are obligate heterozygotes (carriers) for a pathogenic variant in APRT.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier of an APRT pathogenic variant.

Carrier Detection

Carrier testing for at-risk family members is possible if the pathogenic variants in the family have been identified.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Testing of at-risk asymptomatic sibs of individuals with APRT deficiency is possible after molecular genetic testing has identified the specific pathogenic variants in the family. Because an effective treatment is available, this testing is appropriate to consider for at-risk sibs regardless of age. However, such testing should be performed in the context of formal genetic counseling, and is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the APRT pathogenic variants have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although decisions about prenatal testing are the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the APRT pathogenic variants have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Adenine Phosphoribosyltransferase Deficiency: Genes and Databases

GeneChromosome LocusProteinLocus SpecificHGMD
APRT16q24​.3Adenine phosphoribosyltransferaseAPRT databaseAPRT

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Adenine Phosphoribosyltransferase Deficiency (View All in OMIM)

102600ADENINE PHOSPHORIBOSYLTRANSFERASE; APRT
614723ADENINE PHOSPHORIBOSYLTRANSFERASE DEFICIENCY; APRTD

Gene structure. APRT spans 2.8 kb of genomic DNA. The gene contains 5 exons and has a coding region of 540 bp. For a detailed summary of gene and protein information, see Table A, Gene.

Benign allelic variants. Fourteen benign allelic variants have been identified in the sequences flanking APRT [Sahota et al 2001]. Six of these normal variants were located in a 1.2-kb fragment upstream of the initiation codon and eight were located in a 1.8-kb fragment downstream of the termination codon. The majority were identified in both white and Japanese individuals. In addition, four normal variants in introns have been reported in individuals from Japan.

All affected individuals of Japanese ancestry with the c.329G>A (p.Trp98Ter) pathogenic variant examined to date have a silent base substitution at codon 99 (GCC to GCT, Ala).

Pathogenic allelic variants. APRT deficiency is caused by homozygous or compound heterozygous mutations within APRT. A subset of the pathogenic allelic variants are listed in Table 2. More than 40 pathogenic variants have been identified in the coding region of APRT in over 300 affected individuals from more than 25 countries, including at least 200 individuals from Japan. Approximately 10% of mutant alleles in affected white individuals and 5% in affected Japanese individuals remain to be identified [Sahota et al 2001, Bollée et al 2010]. Pathogenic variants include missense, frameshift, and nonsense variants and small deletions/insertions ranging in size from one to eight base pairs.

The most common pathogenic variants in affected white individuals are:

The three most common pathogenic variants in affected Japanese individuals, in order of decreasing frequency, are:

  • c.407T>C, in exon 5
  • c.294G>A, in exon 3
  • c.258_261dupCCGA, in exon 3

Large deletions and contiguous gene rearrangements

  • A contiguous gene deletion of APRT and GALNS can result in APRT deficiency and Morquio syndrome. One affected individual from the Czech Republic who was homozygous for a contiguous gene deletion involving APRT and GALNS has been reported [Wang et al 1999]. The size of the deletion was approximately 100 kb and it spanned the region distal to GALNS exon 2 and proximal to APRT exon 3.
  • A Japanese individual with hemizygosity for APRT and GALNS has been reported [Fukuda et al 1996]. A single nucleotide variant in the other GALNS allele accounted for the loss of GALNS activity. A second mutant APRT allele was not identified and the individual was not reported to be symptomatic for APRT deficiency.
  • A 254-kb deletion was reported in two families: one from Austria and the other from Italy [Menardi et al 1997, Di Pietro et al 2007].

Table 2.

Selected APRT Allelic Variants

Variant ClassificationDNA Nucleotide Change
(Alias 1, 2)
Protein Amino Acid Change
(Alias 1)
Reference Sequences
Benignc.297C>Tp.Ala99= 3
(Ala99Ala)
NG_008013​.1
NM_000485​.2
NP_000476​.1
Pathogenicc.400+2dupT
(400+2insT)
(IVS4+2insT)
c.194A>T
(1350A>T)
p.Asp65Val
c.407T>C
(2066T>C)
p.Met136Thr
c.294G>A
(1450G>A)
p.Trp98Ter
c.258_261dupCCGA
(1415_1418 insCCGA) 4
p.Lys88ProfsTer23
(Arg87PfsTer23)
c.448G>T
(2107G>T)
p.Val150Phe
c.517_519delTTC
(2179_2181 TTC deletion)
p.Phe174del
c.542G>C
(2201G>C)
p.Ter181Ser

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

2.
3.

p.= designates that protein has not been analyzed, but no change is expected

4.

Normal gene product. APRT is a cytoplasmic enzyme that catalyzes the Mg++-dependent synthesis of 5´-adenosine monophosphate from adenine and 5-phosphoribosyl-1-pyrophosphate (PRPP) [Sahota et al 2001]. The enzyme is a homodimer with each subunit consisting of 179 amino acid residues, yielding a molecular weight of 19,481 Daltons [Sahota et al 2001].

The crystal structure of recombinant human APRT in complex with adenosine monophsophate (AMP) has been determined [Silva et al 2004]. The protein, which comprises nine β-strands and six α-helices, forms three domains:

  • A core that includes the PRPP-binding motif
  • A flexible loop besides the core region which may be involved in the catalytic function
  • A variable region primarily involved in base recognition

From studies based on the crystallized enzyme in relation to clinically relevant pathogenic variants, the investigators predicted that water is an important element for PRPP binding [Silva et al 2004].

Abnormal gene product. APRT activity in red cell lysates from individuals with APRT deficiency is typically less than 1% of control values [Sahota et al 2001]. The two reported exceptions are:

  • The vast majority of affected individuals from Japan who are homozygotes or compound heterozygotes for the p.Met136Thr pathogenic variant, which decreases the affinity for the co-substrate PRPP compared with the wild-type enzyme, while the affinity for adenine is unchanged [Sahota et al 2001]. The wild-type enzyme and the variant enzyme with the p.Met136Thr pathogenic variant have the same isoelectric point, but both forms can be detected by electrophoresis or by the increased Km for PRPP for the mutant enzyme.
  • An individual of northern European heritage who had considerable residual enzyme activity in cell extracts but was a compound heterozygote for the c.400+2insT+2insT and p.Val150Phe pathogenic variants [Deng et al 2001]. Enzyme kinetic studies in this individual have not been reported.

APRT heterozygotes. Since APRT is a dimer of identical subunits, individuals who are heterozygous for a null mutation would be expected to have about 25% of normal enzyme activity in cell extracts. In the very few immunochemical studies that have been reported, immunoreactive protein in cell extracts from homozygous APRT-deficient individuals ranged from undetectable to normal, suggesting that, in the first instance, the protein was either not synthesized or was rapidly degraded, and in the second instance, the protein was synthesized but was non-functional.

References

Literature Cited

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Chapter Notes

Author Notes

Vidar Orn Edvardsson, MD, Principal Investigator
APRT Deficiency Research Program

Children´s Medical Center, Office 21-D
Landspitali - The National University Hospital of Iceland
Hringbraut, 101 Reykjavik, Iceland
Tel: +354-543-1000; Fax: + 354-543-3021
E-mail: si.ilatipsdnal@eradiv and si.ilatipsdnal@senotsyendikerar

Runolfur Palsson, MD, Co-Principal Investigator
APRT Deficiency Research Program

Division of Nephrology, Office 14-F
Landspitali - The National University Hospital of Iceland
Hringbraut, 101 Reykjavik, Iceland
Tel: +354-543-1000; Fax: + 354-543-6467
E-mail: si.ilatipsdnal@ruflonur and si.ilatipsdnal@senotsyendikerar

Amrik Sahota, PhD, Consultant
APRT Deficiency Research Program

Department of Genetics
Life Sciences Building
Rutgers University
145 Bevier Road
Piscataway, NJ 08854, USA
Tel: 732-445-7185; Fax: 732-445-1147
E-mail: ude.sregtur.ygoloib@atohas

The official Web site of the Rare Kidney Stone Consortium: rarekidneystones.org

The APRT Deficiency Research Program at Landspitali – The National University Hospital of Iceland, headed by Drs. Vidar Orn Edvardsson and Runolfur Palsson, is a part of the international Rare Kidney Stone Consortium (RKSC) (rarekidneystones.org and rarediseasesnetwork.epi.usf.edu/RKSC/index.htm) which was founded in 2009 with support from the National Institute of Diabetes and Digestive and Kidney Diseases and The Office of Rare Diseases Research at the US National Institutes of Health.

Objectives of the APRT Deficiency Research Program

1.

Establish and expand an APRT Deficiency Registry.

a.

Collection of longitudinal clinical data to study the epidemiology and natural history of the disorder.

b.

Develop cohorts of well-characterized affected individuals for future clinical studies.

2.

Maintain and expand a biobank (DNA, urine, kidney tissue) at Landspitali – The National University Hospital of Iceland.

a.

All participating individuals will be offered genotyping.

b.

Preparation for studies on the potential influence of modifying genes on the clinical expression of the disease.

3.

Increase awareness of APRT deficiency and facilitate timely diagnosis and treatment.

a.

APRT Deficiency Support Network (APRTd.org) is an advocacy organization serving affected individuals and their families that was established early in 2011 with support from the APRT Deficiency Program.

b.

Interaction with advocacy organizations, health care professionals and researchers facilitated through our website to further enhance the educational mission of this project and disseminate knowledge to the community.

c.

Urinary DHA assay development

i.

Development of a UPLC-MS/MS method for diagnostic evaluation and monitoring of pharmacotherapy is in progress.

ii.

Current work focuses also on the development of a urinary DHA screening assay for use in clinical laboratories.

4.

Identify APRT deficient patients at high risk of progressive loss of kidney function and stone formation.

a.

Generate robust longitudinal outcome data through establishment of a prospective cohort of patients with APRT deficiency.

The study is actively recruiting affected individuals from all around the world for the Registry and Biobank Protocols (RDCRN Protocols # 6401 and #6404).

Acknowledgements

Authors V Edvardsson and R Palsson gratefully acknowledge the support of the Rare Kidney Stone Consortium (5U54DK083908-07), a part of the National Center for Advancing Translational Sciences (NCATS) Rare Diseases Clinical Research Network (RDCRN). RDCRN is an initiative of the Office of Rare Diseases Research (ORDR). The Rare Kidney Stone Consortium is funded through a collaboration between NCATS and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). We thank Hrafnhildur Linnet Runolfsdottir, Medical Student, Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland, for generating the images of the urinary DHA crystals, and Sverrir Hardarson, MD, Department of Pathology, Landspitali – The National University Hospital of Iceland, for providing the photomicrographs of the kidney biopsy specimens.

Revision History

  • 18 June 2015 (me) Comprehensive update posted live
  • 30 August 2012 (me) Review posted live
  • 2 May 2012 (ve) Original submission
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